Abstract
We previously demonstrated that IL4, IL13, CLCA1, and CCL26 mRNA were significantly upregulated in the lungs of pigs given a low dose of all trans-retinoic acid (ATRA) and infected with Ascaris suum. We also demonstrated that in vitro ATRA induced a state of partial alternative activation in porcine macrophages (Mφs) and amplified certain aspects of M2a activation induced by IL-4. Given these results, we tested the effect of ATRA on IL-4 responses in two porcine intestinal epithelial cell lines, IPEC1 and IPEC-J2 and observed that ATRA increased mRNA for the IL-4 receptor alpha chain. ATRA also increased IL-4 induced phosphorylation of signal transducer and activator of transcription 6 (STAT6) and mRNA expression of the chloride channel, calcium activated, family member 1 (CLCA1), important for mucus formation, and chemokine (C-C motif) ligand 26 (CCL26), a potent eosinophil chemoattractant. We extended these findings to human Mφ THP-1 cells and showed that ATRA synergistically increased IL-4–induced CCL2, CCL13, and CCL26 mRNA and protein levels. Transglutaminase 2 mRNA, protein, and enzyme activity were synergistically induced in THP-1 cells pretreated with ATRA and then treated with IL-4, thus, ATRA increased signaling in response to IL-4 in porcine epithelial cells and porcine and human Mφs. Given the prevalence of allergic and parasitic diseases worldwide and the close similarities in the porcine and human immune responses, these findings have important implications for the nutritional regulation of allergic inflammation at mucosal surfaces.
Highlights
Vitamin A (VA) is required for T helper 2-associated responses that are shared by immune responses to allergens and parasites [1,2,3]
We observed that IL4, IL13, CLCA1, and CCL26 mRNA were significantly up regulated in the lungs of A. suuminfected pigs given low dose of all trans-retinoic acid (ATRA) [7], indicating that ATRA enhanced the parasite-induced Th2 response
As there are no porcine lung epithelial cell lines available and Ascaris induced a Th2 response in the ileum of infected animals [38], we examined the effect of ATRA on interleukin 4 (IL-4) induced gene expression in two porcine, non-transformed, small intestinal epithelial cell lines, IPEC-1 and IPEC-J2
Summary
Vitamin A (VA) is required for T helper 2-associated responses that are shared by immune responses to allergens and parasites [1,2,3]. ATRA inhibited LPSinduced TNF, CCL3, and CCL4 mRNA and protein levels in human primary Mφs and THP-1 cells [12, 13]; but had no effect on IL1A or IL1B mRNA [13]. Lee et al demonstrated that ATRA increased IL-4 induced arginase 1 (Arg1) mRNA, protein expression, and enzymatic activity in mouse RAW264.7 Mφs [17]. It had no effect on IL-4 induced mannose receptor; C type 1 (Mrc1) or chitinase 3-like 3 (Chi3l3/Ym1) mRNA expression. In porcine epithelial cells and porcine and human Mφs, ATRA increased signaling in response to IL-4 suggesting that ATRA treatment induces a conserved response across cell types and species
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